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Lauzacco, Italy

Huang H.,Laval University | Priori S.G.,University of Pavia | Napolitano C.,Molecular Cardiology | O'Leary M.E.,Philadelphia University | Chahine M.,Laval University
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2011

Long QT syndrome type 3 (LQT3) has been traced to mutations of the cardiac Na+ channel (Nav1.5) that produce persistent Na + currents leading to delayed ventricular repolarization and torsades de pointes. We performed mutational analyses of patients suffering from LQTS and characterized the biophysical properties of the mutations that we uncovered. One LQT3 patient carried a mutation in the SCN5A gene in which the cysteine was substituted for a highly conserved tyrosine (Y1767C) located near the cytoplasmic entrance of the Nav1.5 channel pore. The wild-type and mutant channels were transiently expressed in tsA201 cells, and Na+ currents were recorded using the patch-clamp technique. The Y1767C channel produced a persistent Na+ current, more rapid inactivation, faster recovery from inactivation, and an increased window current. The persistent Na+ current of the Y1767C channel was blocked by ranolazine but not by many class I antiarrhythmic drugs. The incomplete inactivation, along with the persistent activation of Na+ channels caused by an overlap of voltage-dependent activation and inactivation, known as window currents, appeared to contribute to the LQTS phenotype in this patient. The blocking effect of ranolazine on the persistent Na+ current suggested that ranolazine may be an effective therapeutic treatment for patients with this mutation. Our data also revealed the unique role for the Y1767 residue in inactivating and forming the intracellular pore of the Nav1.5 channel. Copyright © 2011 the American Physiological Society. Source


Tarone G.,University of Turin | Balligand J.-L.,Catholic University of Louvain | Bauersachs J.,Medizinische Hochschule Hanover | Clerk A.,University of Reading | And 12 more authors.
European Journal of Heart Failure | Year: 2014

The failing heart is characterized by complex tissue remodelling involving increased cardiomyocyte death, and impairment of sarcomere function, metabolic activity, endothelial and vascular function, together with increased inflammation and interstitial fibrosis. For years, therapeutic approaches for heart failure (HF) relied on vasodilators and diuretics which relieve cardiac workload and HF symptoms. The introduction in the clinic of drugs interfering with beta-adrenergic and angiotensin signalling have ameliorated survival by interfering with the intimate mechanism of cardiac compensation. Current therapy, though, still has a limited capacity to restore muscle function fully, and the development of novel therapeutic targets is still an important medical need. Recent progress in understanding the molecular basis of myocardial dysfunction in HF is paving the way for development of new treatments capable of restoring muscle function and targeting specific pathological subsets of LV dysfunction. These include potentiating cardiomyocyte contractility, increasing cardiomyocyte survival and adaptive hypertrophy, increasing oxygen and nutrition supply by sustaining vessel formation, and reducing ventricular stiffness by favourable extracellular matrix remodelling. Here, we consider drugs such as omecamtiv mecarbil, nitroxyl donors, cyclosporin A, SERCA2a (sarcoplasmic/ endoplasmic Ca2 + ATPase 2a), neuregulin, and bromocriptine, all of which are currently in clinical trials as potential HF therapies, and discuss novel molecular targets with potential therapeutic impact that are in the pre-clinical phases of investigation. Finally, we consider conceptual changes in basic science approaches to improve their translation into successful clinical applications. © 2014 The Authors. Source


Priori S.G.,Molecular Cardiology | Priori S.G.,University of Pavia
Indian Heart Journal | Year: 2014

It is known that monogenic traits may predispose young and otherwise healthy individuals to die suddenly. Diseases such as Long QT Syndrome, Brugada Syndrome and Arrhythmogenic Right Ventricular Cardiomyopathy are well known causes of arrhythmic death in young individuals. For several years the concept of "genetic predisposition" to sudden cardiac death has been limited to these uncommon diseases. In the last few years clinical data have supported the view that risk of dying suddenly may cluster in families, supporting the hypothesis of a genetic component for sudden cardiac death. In this review I will try to provide an overview of current knowledge about genetics of sudden death. I will approach this topic by discussing first where we stand in the use of genetics for risk stratification and therapy selection in monogenic diseases and I will then move to discuss the contribution of genetics to patient profiling in acquired cardiovascular diseases.© 2013, Cardiological Society of India. All rights reserved. Source


Knoll R.,Center for Research Excellence | Iaccarino G.,University of Salerno | Tarone G.,University of Turin | Hilfiker-Kleiner D.,Molecular Cardiology | And 4 more authors.
European Journal of Heart Failure | Year: 2011

Many primary or secondary diseases of the myocardium are accompanied with complex remodelling of the cardiac tissue that results in increased heart mass, often identified as cardiac 'hypertrophy'. Although there have been numerous attempts at defining such 'hypertrophy', the present paper delineates the reasons as to why current definitions of cardiac hypertrophy remain unsatisfying. Based on a brief review of the underlying pathophysiology and tissue and cellular events driving myocardial remodelling with or without changes in heart dimensions, as well as current techniques to detect such changes, we propose to restrict the use of the currently popular term 'hypertrophy' to cardiac myocytes that may or may not accompany the more complex tissue rearrangements leading to changes in shape or size of the ventricles, more broadly referred to as 'remodelling'. We also discuss the great potential of genetically modified (mouse) models as tools to define the molecular pathways leading to the different forms of left ventricle remodelling. Finally, we present an algorithm for the stepwise assessment of myocardial phenotypes applicable to animal models using well-established imaging techniques and propose a list of parameters most suited for a critical evaluation of such pathophysiological phenomena in mouse models. We believe that this effort is the first step towards a much auspicated unification of the terminology between the experimental and the clinical cardiologists. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2011. For permissions please email: journals.permissionsoup.com.2011 © Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2011. For permissions please email: journals.permissionsoup.com. Source


Kashimura T.,University of Manchester | Briston S.J.,University of Manchester | Trafford A.W.,University of Manchester | Napolitano C.,Molecular Cardiology | And 5 more authors.
Circulation Research | Year: 2010

Rationale: Mutations of the ryanodine receptor (RyR) cause catecholaminergic polymorphic ventricular tachycardia (CPVT). These mutations predispose to the generation of Ca waves and delayed afterdepolarizations during adrenergic stimulation. Ca waves occur when either sarcoplasmic reticulum (SR) Ca content is elevated above a threshold or the threshold is decreased. Which of these occurs in cardiac myocytes expressing CPVT mutations is unknown. Objective: We tested whether the threshold SR Ca content is different between control and CPVT and how it relates to SR Ca content during β-adrenergic stimulation. Methods and results: Ventricular myocytes from the RyR2 R4496C +/- mouse model of CPVT and wild-type (WT) controls were voltage-clamped; diastolic SR Ca content was measured and compared with the Ca wave threshold. The results showed the following. (1) In 1 mmol/L [Ca]o, β-adrenergic stimulation with isoproterenol (1μmol/L) caused Ca waves only in R4496C. (2) SR Ca content and Ca wave threshold in R4496C were lower than those in WT. (3) β-Adrenergic stimulation increased SR Ca content by a similar amount in both R4496C and WT. (4) β-Adrenergic stimulation increased the threshold for Ca waves. (5) During β-adrenergic stimulation in R4496C, but not WT, the increase of SR Ca was sufficient to reach threshold and produce Ca waves. Conclusions: In the R4496C CPVT model, the RyR is leaky, and this lowers both SR Ca content and the threshold for waves. β-Adrenergic stimulation produces Ca waves by increasing SR Ca content and not by lowering threshold. © 2010 American Heart Association, Inc. Source

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